Concentrated foam-producing spermicides



United. States Patent CONCENTRATED FOAM-PRODUCING SPERIVHCIDES NathanielM. Elias, 56 Washington Mews, New York, N.Y.

N Drawing. Filed June 23, 19 59, Ser. No. 822,202

20 Claims. (Cl. 167-58) This application is a continuation-in-part of mycopending application, S.N. 308,289, filed September 6, 1952, nowabandoned.

The present invention relates to compositions adapted chiefly for use astopical remedies in contact with the mucous membranes in the vaginalcavity and to a method of preparing such a composition. The topicalremedies of this invention comprise concentrated spermicidalcompositions which are designed for use with moistened sponges orsponge-like masses such as tampons, rubber sponges, marine sponges,cellulose sponges, sponges made of cellular plastic material, etc., andwhich produce foam while in use.

One of the chief drawbacks to the use of spermicides has been theircost. One object of the present invention is to provide a highlyconcentrated spermicidal material which may be diluted with water justbefore use, which can be applied without the use of complex andexpensive applicators, and which is not irritating to the membranes inuse. The use of such highly concentrated spermicidal material cuts downpaskaging, handling and shipping costs.

I have found that the use of a sponge or sponge-like mass, moistenedwith suflicient water to dilute the nonirritating concentratedspermicide, will give a satisfactory means for reducing the cost ofapplication, provided (1) sufiicient spermicidal power is inherent inthe concentrated spermicide, (2) suflicient foam is produced by thespermicide to distribute it thoroughly throughout the vaginal canal, and(3) the composition mixes quickly with seminal fluid. The foam producingproperty is highly important as a means of distribution of thespermicidal liquid. The moist sponge acts as a vehicle for distributionof the spermicidal liquid and as a reservoir for foam production.

I have also found that concentrated solutions of high spermicidal andfoam-producing power may be obtained which are not irritating. This maybe done with certain water-soluble non-ionic and foam-forming agentswhose pH can be regulated to any point required and solutions of whichare compatible with various salts and acids. These products which I havefound to possess high spermicidal power are sufliciently foam-formingonly in the absence of insoluble ingredients and belong to the classrepresented by the generic formula R OCHzOHz O 011101191011 irritationin use with a moistened sponge.

average value between 8 and 12. In the preferred specific embodiment ofmy invention x is approximately 9.75, R is either the triisopropyl groupor the tetraethyl group and is in the para position and R is hydrogen;

Generally R may have from 1 to 23 carbon atoms and R may have fiom O to23 carbon atoms except that the sum of the carbon atoms in R and Rshould not be less than 4 or more than 23.

An important advantage of using these materials is the fact thatsolutions containing them are neutral and may be adjusted to any pHvalue, and that they do not react with weak acids or alkalis or withbuifer salts or neutral salts.

The quantity of active spermicide described above in Formula 1 which maybe employed in the present composition will vary considerably. In apreferred practice of this invention it will constitute from 15 to byweight of the total composition.

I have found that certain neutral salts such as sodium or potassiumchloride or sulfate or other similar salts are valuable additions tothese compositions in that they increase enormously the speed ofmiscibility of the nonionic foam-forming spermicidal materials withseminal fluid so that quick spermicidal action is assured. These neutralsalts desirably constitute 5% to about 20% by weight of the spermicidalcomposition.

By using the materials of this invention, I have found it easilypossible to make solutions, 30 grams of which are ample for 60 or moreapplications, free of resulting Even higher concentrations arepracticable.

The method of application is simple also in that a glass, plastic,wooden or similar rod may be moistened with the solution and then rubbedon the moistened sponge. This may be repeated three or four times, thematerial being applied on all sides. For example, /2 cc. may be sotransferred very quickly and easily. As an example of the sponge masswhich may be used, a sheet of rubber sponge about thick by 2" squarewould be suitable. It will act as a reservoir for 3-5 cc. of water.After the transfer of the spermicidal and foam-forming concentrate toit, it is slightly compressed and released several times to mix thesolution into the water in the sponge. It thus distributes theconcentrated liquid throughout the water stored in the sponge beforeinsertion. It is of course also possible to apply the concentratedliquid to the sponge in other Ways, such as by the use of an eyedropper, dropping tube, scoop or brush. It is generally convenient tohave the means of applying the liquid to the sponge attached to theclosure of the container and extending into said container.

Tests have shown that the moisture in the sponge, as used, may rangebetween /2 cc. and 3 cc. so that when a solution containing 15% of theactive spermicidal agent is applied to the sponge in an amount of A2cc., the resulting concentration which is used topically may range from7 /2% to 2.14%. If a 20% solution is applied to the wet sponge underthese conditions in the amount of /2 cc., the resulting solution whichis used topically may range from 10% to 2.86%.

I am aware that some of the polyglycol monoethers of alkyl phenols havebeen'used in spermicidal jellies and suppositories. However, they havealways been used in the presence of insoluble materials such asricinoleic acid, glyceryl moonlaurate, vegetable and other gums, etc.,or in the presence of strong spermicidal materials such as phenylmercuric acetate, etc., to enhance the eifectiveness of these otherspermicides. There has been no disclosure that they are spermicidal inthemselves not that they can be used in high concentrations withoutcausing irritation. In addition, the presence of insoluble materialsinhibits foam formation so that the: teaching of these previousdisclosures would be insufiicient for the development of the presentinvention since foam formation is essential to its proper functioning. Ihave now found it possible to obtain with these materials both highsperrni: cidal power and high foam-forming power simultaneously Withoutthe use of heavy metal or other spermicides.

In addition, by' using aneutral salt such as sodium chloride inconjunction with these materials,- I have found a great increasein thespeed of, mixing of the spermicide withv semenfthus resulting in 'asubstantial increase in efiectiveness. V 7

' Glycerine; propylene glycol or ,other polyhydroxy compoundsor urea maybe added to any of the formulae in theexamplesgiven below to preventfreezing in cold Weather. 7

Since no gums are present in any of the formulae nor any substanceswhich may cause mold formation, no mold inhibiting material is necessaryfor this purpose. However, such substances as methyl, ethyl, propyl orbutyl parahydroxy benzoate, oxyquinoline sulfate, phenols, alkylphenols, chlorinated phenols, chlorinated thymols, the alkali alkylsulfate, etc., may be used for their bacten'iostatic and fungistaticeffect;

Water soluble acids with or without buffer salts may be used to regulatethe pH value. The pH value of the compositions of'the present'inventionmay range'bc tween 1 and 8.5although'a pH of about 4.5 (the nor= mal'pH-ofthe vaginal membranes) is preferred. The limitations on the pH areplacedin this range simply because in this range the chances ofirritation are less than at higher or lower pH values and a pH in thisrange is less favorable for invasion by undesirable organisms.

' The acids which may be used include among others lactic, boric,acetic, tartaric, etc;, and the buffer salts include sodium or'potassiumsalts 'of these acids as well as of'phosphori'c acid and others. j p

The following are typical examples of concentrated foam-producingspermicidal compositions suitable for effective use with a wet spongemass or tampon.

Example 1 Parts by wgt.

p-Triisopro'pyl phenyl monoether of nona ethylene Water sufficient tomake a total of 100.00 parts by weight.

Example 2 A concentrated foam-producing spermicidal composition havingthe same formula as Example 1 but in which the p-triisopropyl phenylmonoether of nona ethylene glycol is replaced with a mixture consistingof the p-triisopropyl phenyl monoether of nona ethylene glycol and thep-triisopropyl phenyl monoether of dodecaethylene glycol.

Example 3 A concentrated foam-producing spermicidal composition havingthe same formula as Example 1 but in which the p-triisopropyl phenylmonoether of nona ethylene glycol is replaced by p-tetraethyl phenylmonoether of dodecaethylene glycol. r r i V 1 Example 4 A concentratedfoam-producing spermicidal composition having the same formula asExample 1 but in which part of the p-triisopropyl phenyl monoether ofnona ethylene glycol is replaced by p-tetraethyl phenyl monoether ofnona ethylene glycol. 7

Example p A concentrated foam-producing spermicidal composition havingthe same formula as Example l'except that the proportion of sodiumchloride is increased from 5% to 10%.

Example 6 A concentrated foam-producing spermicidal composition havingthe same formula as Example 1 in which the lactic acid is replaced by1.5 parts of boric acid.

Example 7 A concentrated foam-producing spermicidal composition havingthe same formula as Example 1 in which the lactic acid is replaced by1.5 parts of boric acid and the sodium lactate is replaced by 1.5 partsof sodium borate.

When /2 cc. of any of the compositions described in the above examplesis applied to a sponge containing 5 cc. of water, the resulting solutioncomes well within the spermicidal requirements recommended by theCouncil of Pharmacy of the A.M.A., using the Brown & Gamble technique.

The compositions included in this invention may be shipped constitutedas described in the aforesaid examples or may be shipped in even moreconcentrated form to remote countries or localities and there they maybe diluted and packed in containers of local origin. The following areexamples of such higher concentrates.

SHIPPING CONCENTRATES Example 8 p-Triisopropyl phenyl monoether of nonaethylene glycol -a- Lactic acid 3.0 Sodium lactate 3.0 Sodium chlorid10.0

Water sufiicient to make a total of 100.0.

Example 8 is twice the concentration of Example 1. On arriving at itsdestination, it may be diluted with an equal quantity of water, givingthe formula of Example 1.

Water sufficient to make 100.0.

Example 9 requires the addition of 300 parts of a sodium chloridesolution containing 15 parts of salt to ob tain a composition identicalwith that in Example 1 Example 10 p-Triisopropyl phenyl monoether ofnona ethylene glycol a V Boric acid 5 Sodium chloride 20 On dilutingthis with 400 parts of water there would be obtained a product suitablefor use containing: p-Triisopropyl phenyl monoether of nona ethylene y lw 7 7 15 Boric acid Sodium chloride 4 It is obvious that by using suchconcentrates for shipping purposes freight, container and other shippingcosts are greatly reduced.

Example 11 p-Triisopropyl phenyl monoether of nona ethylene I V glycol20 Boric acid 1 7 3 Sodium chloride 1'6 Water suific-ient to make 100.

v Example 12 p-Triisopropyl phenyl monoether of nona ethylene glycol 20Boric acid 3 Propyl p-hydroxybenzoate .2 Sodium chloride Watersufficient to make 100.

The spermicidal composition of the present invention may be prepared forapplication to a sponge-like mass by mixing a concentrated watersolution of a non-ionic, foam-producing, surface active agent of theclass represented by the formula Parts by wgt.

p-Triisopropyl phenyl monoether of nona ethylene glycol Lactic acid 1.5Sodium lactate 1.5 Sodium chloride 5 Water suflicient to make a total of100 parts by weight.

The Brown & Gamble technique consists of mixing one part of thespermicidal material with four parts of physiological saline solution.The resulting mixture is then mixed on a slide with an equal volume ofhuman semen and the time for complete immobilization is observed.

One-half cc. of the above composition was mixed with 5 cc. of water in asponge, after which 1 part of the resulting solution was taken from thesponge and diluted with 5 parts of physiological saline solution. Onepart of this final solution was then mixed with an equal volume of humansemen on a slide, and the time for complete immobilization was observed.

Complete immobilization of the sperm resulted in less than five minutes.

The effectiveness of said solution comes well within the spermicidalrequirements recommended by the Council of Pharmacy of the AmericanMedical Association using the Brown & Gamble technique. This requirementis that immobilization occur in thirty minutes or less.

The clinical safety of the compositions of the present invention weretested by the Margaret Sanger Research Bureau. The spermicide tested hadthe following composition:

7 Parts by wgt. p-Triisopropyl phenyl monoether of nona ethylene glycolBoric acid 3 Propyl p-hydroxybenzoate .2 Sodium chloride 10 Watersufiicient to make 100 parts by weight.

examination was performed and all findings were recorded. Particularattention was paid to the condition of the vulva, vaginal and cervicalmucosa. The women were instructed to insert the foam filled spongenightly for a period of 21 days. A string was attached to the sponge foreasy removal. The patient was instructed to make a careful note of anyevidence of irritation. Vaginal examinations were made twice weekly aswell as after the test period was completed and all objective findingswere recorded.

There was no complaint of irritation in 11 patients. One complained ofslight itching.

There were no objective signs of irritation in any of the 12 subjects.

To further test the clinical safety and efiectiveness of the presentcomposition the following clinical experiments were carried out at theSt. Elizabeth Health Department in Black River, Jamaica, B.W.I. Thespermicidal composition used in these experiments are identified asDuratoam Liquid and consists of a water solution containing In saidclinical experiment Durafoam Liquid was distributed to patients withinstructions as to its use. It was dispensed with a small sponge and thepatients were instructed that said sponge is to be moistened on bothsides with /2 cc. of said Durafoam Liquid before insertion and use. TheDurafoam Liquid was distributed to patients in a small dropper bottle tomake measurement easy and the patients were instructed to bring thebottles back to be refilled. The patients were instructed to return whenthey required additional material. The public health nurses of St.Elizabeth Health Department were used in this experiment fordistribution of the Durafoam Liquid and to follow up patients who wereusing it.

Set forth below in Table I is a report of the above described clinicalexperiment covering a period of 18 months.

TABLE I Total patients given Durafoam Liquid with sponge 640 Totalpatients discontinued use of Durafoam Liquid Multiplying the figure 571by 9 and dividing by 12 gives 428 woman years use with 18 pregnancies.This is 4.2 pregnancies per 100 woman years. The normal rate in thispopulation is between 70 and per woman years. The Durafoanr Liquidtherefore reduces the pregnancy rate very substantially. Of the 69patients who discontinued the use of the method 18 became pregnant. Ofthese 18, 12 admitted irregular use and 4 stated that their husbandsobjected to the presence of the sponge. Fifty-one discontinued eitherbecause they were planning a pregnancy or were indifferent and did notwant to be bothered with using the method.

Theresults of these tests indicate that the present spermicidalcomposition with sponge is a very effective method for reducing thepregnancy rate and is well adapted for use in rural areas whereeducation is at a low level. It is also quite evident that the alkylphenoxy polyethoxyethanols are highly and eifectively spermicidal in useand especially so in the presence of a salt.

While the invention has been described with particular reference tospecific embodiments, it is to be understoodthat it is not limitedthereto, but is to be construed broadly 7 and restricted solely by thescope of the appended claims.

What is claimed isi: r 1'. spermicidalcomposition consistingessentiallyofa buttered pharmaceutical vehicle and asi'chief spermicidal ingredientan alkylplienoxypolyethoxyethanol of the formula QUIET- 2 lix-C 2) x011.

hydrogen, and R is para to the group OCH CH (OCH CH OH and from &to,12carboncatoms in the chain, andxhas ahfaveragevalue. oftromabouLG. to.about. 12. i A

'3. A composition according tosclaim 2. wherein said,compositionasiappliedtopically.contains from about 2%. to 10%. of said.alkylphenoxypolyethoxyethanol.

I41 A composition; according to claim 1 wherein. thealkylphenoitypolyethoxy thanol is, a mixture of,p-alkylphenoiiypolyethokyethanols wherein'R is hydrogen,

andR has from 8to 12.-carbon, atomsin the chain and x r average'value oifrom'about 6, to about 12. 5. composition' according; tojclaim 1 whereinsaid chief spermicidal'iii'gredient is -p-triisopropyl phenylrnonorether" ofrioriafethyleneglycol. 5 i

6Q A'spermic'idab'coniposition according to claim 1 wherein thevehicleicontains' T si rmiidal .compos tio according to l i l whereinsaid vehicle'contain's' bofic acid.

8. A spermicidal compositionconsisting essentially, of

a, buffered pharmaceutical vehicle and containing, as; its

chief spermicidal active ihgredie'nt a 'com'pouiid the,

general formula vh ia RI e esents, a lk l group hav from 1 to 23 carbonatoms in th e chain and R represents a member q e irqml q as u s st a ol y up v from [to '23 carbon atoms and hydrogen, and x has an averagevalue of from about 5 to about 12, and wherein saideomposition'havihg apH in the range about 1 to about 85 inclusive.

a 9, A composition according to claim 8 wherein the spemiicidally.active ingredient is present in the rangeof about 15. to 75% by weightofthespermicidal compositlon. a

1 0.. A composition accordingto claim' 8 wherein the spermlcidallyactive ingredient is present in an amount of. 15% by weight ofthespermicidalcomposition.

11. A spermicidal composition according to claim 8wheremithespermicidally active ingredient is present in an amount of'30bjweight of the spermicidal composition.

,12. Aispehmicidal composition according to claim 8 wheremspermicidallyfactive ingredient is present in 8 an amount of 60% byweight of the spermicidal composition.

13. A spermicidal composition accordingv to whereinthe'spermicidallyactive ingredient is presentzin the" amount of by wight'ofthe 'spermicidalcomposi;

tionJ i "14. A spermicidal composition consisting essentially of ahydrous pharmaceutical vehicle containing as it's;

chief spermicidally active ingredient a compound 'of the a generalformula wherein R represents an alkyl group having from 1 to 23 carbonatoms in, the chain and R represents a member selected from the classconsisting of alkyl groups having from 1 ito 23 carbon atoms andhydrogen, and x has an average valueof from about itoabout 12, andwherein the. of. thecarbon atoms :i n.. R andR; is not.

4 or greater 23, saidspefrmicidally active ing riedient;

asere sm- 5} 3 s d atema t a sent i ng sti n ha ng. a 12H; n e an e ir nabout 1 to about inclusive.

15. A spermicidal composition consisting essentially oi a tte e rmaswfia i e-an ta n te- 1 plied topically, from 2% to. 1 0% of a compou dfofgen; eral formula i m wherein R represents an alkyl group having from 13,223

carbon atomsin the chain and li frepresents agmenrber,

OCHr-CH2(O orig-501191011;

wherein R. represents, an, alkyl: group. haying from 1: 19. 2.3: carbon:atoms inrthe chain andR represents a, member; selected, from the classconsisting of alkyl groups, haying, from 1 to.23 carbon atoms andhydrogen, and x hasgan j average, value of firomabout 5. to about, 12,and;wherein the sum of the carbonatomsinR; and; R is .n o,t less than 4or greater than 23, said; concentrate, J i u i nthe water in the moistsponge, having a pH in therange from about; 1, to about 8.5 inclusive.

17; A. spermicidal method: which comp isi app y n toa wet, sponge-like.mass avliquid,snermi iial QQI QQ Y trate containing. a neutralsalt and f-he chief. nemiq h ally active ingredientv av compound; of; thegeneralfo1;-,, mula, 7

from 1 to 23 carbon atoms andghydrogen, and x hast average value of fromabout 5 to 12, and wherein the sum of the carbon atoms in R and R is notless than 4 or greater than 23, and applying the resulting spermicidallytreated sponge-like mass into the vaginal cavity in contact with themucous membranes to serve as a topical remedy.

18. A spermicidal method which comprises introducing into the vaginalcavity a spermicidal composition consisting essentially of apharmaceutical carrier and as chief spermicidal ingredient analkylphenoxypolyethoxyethanol of the formula O CHr-CH (O GH -CHI) :OH

wherein R represents an alkyl group having from 1 to 23 carbon atoms inthe chain and R represents a member selected from the class consistingof alkyl groups having from 1 to 23 carbon atoms in the chain andhydrogen, and x has an average value of from about 5 to about 12, andwherein the sum of the carbon atoms in R and R is not less than 4 orgreater than 23.

19. A method according to claim 18 wherein R ishydrogen and R is para tothe group and has from 8 to 12 carbon atoms in the chain, and x has anaverage value of from about 6 to about 12.

29. A method according to claim 19 wherein said composition as appliedtopically contains from about 2% to 10% of saidalkylphenoxypolyethoxyethanol.

References Cited in the file of this patent UNITED STATES PATENTS1,970,578 Schocller et a1 Aug. 21, 1934 2,213,477 Steindorff et al Sept.3, 1940 2,436,184 Stillman et a1 Feb. 17, 1948 2,467,884 Elias Apr. 19,1949 2,541,103 Sander Feb. 13, 1951 2,556,567 Wright June12, 19512,889,250 Mende et a1. June 2, 1959 OTHER REFERENCES De Vilbiss: J.Contraception, January 1938, pp. 7-9 and 19.

N.N.R.: 1951, Phila., Pa, pp. xxxi-mii.

1. A SPERMICIDAL COMPOSITION CONSISTING ESSENTIALLY OF A BUFFEREDPHARMACEUTICAL VEHICLE AND AS CHIEF SPERMICIDAL INGREDIENT ANALKYLPHENOXYPOLYETHOXYETHANOL OF THE FORMULA